The search for genes that cause or contribute to Parkinson's disease (PD) has intensified since the discovery of alpha-synuclein gene and parkin gene mutations linked to patients with familial Parkinson's disease. NURR1 {the human homolog of roden nurr1), a member of the nuclear receptor super family, may be relevant to the disease since the gene is essential for induction and maintenance of nigra dopaminergic (DAergic) adenotype and heterozygous nurr1 knock-out mice display many features of parkinsonism with aging. To investigate if NURR1 is a susceptibility gene in Parkinson's disease we have performed a case-control study in over 200 PD patients. We have identified two novel variants in NURR1 gene (-291T deletion and -245T ->G substitution) in 10 of 107 proband familial Parkinson's disease (fPD), but not in sporadic PD (sPD, n=94) and age-and race-matched normal controls (NC, n=221). In pedigree analysis of the ten fPD families we have found that all PD patients but none of the non-PD family members have the NURR1 gene variations. A linkage study using 5 haplotype markers in 4 available fPD families suggested that at least two distinct haplotyes exist in these fPD families. Furthermore, we have constructed full-length human NURR1 gene encoding the two variants and demonstrated that the variant genes reduced NURR1 gene expression by >85% when transfected in human embryonic kidney cells HEK293 or in human neuroblastoma cells SH-5YSY. In addition, rate-limited DA synthesis enzyme tyrosine hydroxylase mRNA was significantly low in the SH-5YSY cells transfected with two variant genes. These data suggest that the variants in the NURR1 gene might be PD-related mutations. We, therefore, hypothesize that diminished expression of the NURR1 gene (loss of function), induced by the mutations in the gene, predisposing to DAergic neuron dysfunction, may represents a potentially important risk factor for Parkinson's disease. To test this hypothesis, we propose to study the relationship between the genotype of the mutations and the phenotype of the disease, and to investigate the underlying mechanisms. First (Aim 1), we will assay for the mutations, genotypes, and phenotypes in the first-degree members of all 10 fPD patients with the identified NURR1 mutations to determine the haplotype linkage, relationship between genotype and phenotype. Second (Aim 2), we will investigate if the mutations in NURR1 gene are specific for Parkinson's disease by analyzing the gene mutations in a total of 400 NC, 300 sPD, and 120 non-PD neurological disorders. Finally (Aim 3), we will determine the mechanisms by which the mutant genes alter NURR1 expression and DAergic neuronal dysfunction. The proposed experiments, which will take approximately four years for completion, will be conducted in parallel with a pilot study to generate a mouse model carrying the NURR1 mutations. The outcomes of the proposed study will improve our understanding of the role of NURR1 gene in the pathogenesis of Parkinson's disease, and may lead to potential therapeutic interventions, as well as means for diagnosing individuals having an increased risk of developing the disease.